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Pediatric Considerations
Pregnancy Considerations
Propylthiouracil (PTU) is currently the drug of choice during 1st trimester of pregnancy and methimazole (MMI) is preferred in the 2nd and 3rd trimester. Treat with lowest effective dose. Avoid treatment-induced hypothyroidism. Radioiodine therapy is contraindicated.
EPIDEMIOLOGY
- 1.3% of population
- Predominant sex: female > male (7 to 10:1)
- Predominant age: autoimmune thyroid disease (GD) in 2nd and 3rd decades. TMNG more common in patients >40 years.
Incidence
- Female: 1/1,000
- Male: 1/3,000
ETIOLOGY AND PATHOPHYSIOLOGY
- GD: autoimmune disease
- TMNG: 60% TSH receptor gene abnormality; 40% unknown
- Toxic adenoma: point mutation in TSH receptor gene with increased hormone production
- Thyroiditis:
- Hashitoxicosis: autoimmune destruction of the thyroid; antimicrosomal antibodies present
- Subacute/de Quervain thyroiditis: granulomatous reaction; genetic predisposition in specific human leukocyte antigens; viruses, such as coxsackievirus, adenovirus, echovirus, and influenza virus, have been implicated; self-limited course, 6 to 12 months
- Suppurative: infectious
- Drug-induced thyroiditis: Amiodarone produces an autoimmune reaction and a destructive process. Lithium, interferon-α, and interleukin-2 cause an autoimmune thyroiditis.
- Postpartum thyroiditis: autoimmune thyroiditis that lasts up to 8 weeks and, in 60% of patients, hypothyroidism manifests in the future
Genetics
Concordance rate for GD among monozygotic twins is 35%.
RISK FACTORS
- Positive family history, especially in maternal relatives
- Female
- Other autoimmune disorders
- Iodide repletion after iodide deprivation, especially in TMNG
COMMONLY ASSOCIATED CONDITIONS
- Autoimmune diseases
- Down syndrome
- Iodine deficiency
DIAGNOSIS
HISTORY
- Thyrotoxicosis is a hypermetabolic state in which energy production exceeds needs, causing increased heat production, diaphoresis, and even fever.
- Thyrotoxicosis affects several different systems:
- Constitutional: fatigue, weakness, increased appetite, weight loss
- Neuropsychiatric: agitation, anxiety, emotional lability, psychosis, coma and poor concentration and memory
- GI: increased appetite, hyperdefecation
- Gynecologic: oligomenorrhea, amenorrhea
- Cardiovascular: tachycardia (most common) and chest discomfort that mimics angina
Geriatric Considerations
Apathetic hyperthyroidism in the elderly
PHYSICAL EXAM
- Adults:
- Skin: warm, moist, pretibial myxedema (GD only)
- Head, eye, ear, nose, throat (HEENT): exophthalmos, lid lag
- Endocrine: hyperhidrosis, heat intolerance, goiter, gynecomastia, low libido, and spider angiomata (males)
- Cardiovascular: tachycardia, atrial fibrillation, cardiomegaly
- Musculoskeletal: skeletal demineralization, osteopenia, osteoporosis, fractures
- Neurologic: tremor, proximal muscle weakness, anxiety and lability, brisk deep tendon reflexes
- Rarely: thyroid acropathy (clubbing), localized dermopathy
- Children:
- Linear growth acceleration
- Ophthalmic abnormalities more common
DIFFERENTIAL DIAGNOSIS
- Anxiety
- Malignancy
- Diabetes mellitus
- Pregnancy
- Menopause
- Pheochromocytoma
- Depression
- Carcinoid syndrome
DIAGNOSTIC TESTS & INTERPRETATION
- 95% have suppressed TSH and elevated free T4. Total T4 and triiodothyronine (T3) represent the bound hormone and can be affected by pregnancy and hepatitis. (1)[A]
- T3: elevated, especially in T3 toxicosis or amiodarone-induced thyrotoxicosis: presence of TSH receptor antibody or thyroid-stimulating immunoglobulin is diagnostic of GD
- Free thyroxine index (FTI): calculated from T4 and thyroid hormone-binding ratio; corrects for misleading results caused by pregnancy and estrogens
- Inappropriately normal or elevated TSH with high T4 suspicious for pituitary tumor or thyroid hormone resistance
- Drugs may alter lab results: estrogens, heparin, iodine-containing compounds (including amiodarone and contrast agents), phenytoin, salicylates, steroids (e.g., androgens, corticosteroids)
- Drug precautions: Amiodarone and lithium may induce hyperthyroidism; MMI may cause warfarin resistance.
- Other findings that can occur: anemia, granulocytosis, lymphocytosis, hypercalcemia, transaminase, and alkaline phosphate elevations
Initial Tests (lab, imaging)
- TSH, free T4, T4, T3, thyroid-stimulating immunoglobin (TSI)
- TSH receptor antibodies (TSH-R Abs): The routine assay is the TSH-binding inhibitor immunoglobulin assay (TBII). TSH-R Abs are useful in the prediction of postpartum Graves thyrotoxicosis and neonatal thyrotoxicosis.
- Thyroxine/triiodothyronine ratio: The T4-to-T3 ratio may be a useful tool when the iodine uptake testing is not available/contraindicated. ~2% of thyrotoxic patients have "T3 toxicosis."
- Nuclear medicine uptake and scanning (123I or 131I): The reference-range values for 24-hour radioiodine uptake is between 5% and 25%.
- Increased thyroid iodine uptake is seen with TMNG, toxic solitary nodule, and GD.
- GD shows a diffuse uptake and can have a paradoxical finding of high uptake at 4 to 6 hours but normal uptake at 24 hours because of the rapid clearance.
- TMNG will show a heterogeneous uptake, whereas solitary toxic nodule will show a warm or "hot" nodule.
- In iodine-deficient areas, an increased uptake is associated with low urine iodine levels.
- Causes of thyrotoxicosis with low iodine uptake:
- Acute thyroiditis, thyrotoxicosis factitia, and iodine intoxication with amiodarone or contrast material can cause low-uptake transient thyrotoxicosis. After thyroiditis resolves, the patient can become euthyroid or hypothyroid.
- Iodine loading can cause iodine trapping and decreased iodine uptake (Wolff-Chaikoff effect).
- Thyrotoxicosis factitia: Thyroglobulin levels are low in exogenous intake and high in endogenous production.
- Other extrathyroidal causes include struma ovarii and metastatic thyroid carcinoma.
- Technetium-99m scintigraphy: controversial because it has a 33% discordance rate with radioactive iodine scanning
Follow-Up Tests & Special Considerations
In severe cases, such as thyroid storm, hospitalize until stable, especially if >60 years of age, because of the risk of atrial fibrillation.
Diagnostic Procedures/Other
Neck US will show increased diffuse vascularity in GD.
Test Interpretation
- GD: hyperplasia
- Toxic nodule: nodule formation
TREATMENT
- Decision of which patients to treat and how to treat should be individualized.
- Observation may be appropriate for patients with mild hyperthyroidism (TSH >0.1 or with no symptoms) especially those who are young and with low risk of complications (Afib, osteoporosis).
- Antithyroid medication is contraindicated in patients with thyroiditis. Treatment for subacute thyroiditis is supportive with NSAIDs and β-blockers. Steroids can be used for 2 to 3 weeks (3). GD or TNMG can be managed by either antithyroid medication, RAIT, or thyroidectomy.
- Radioactive iodine therapy (RAIT): most common definitive treatment used in United States for GD and TMNG
- Pretreatment with antithyroid drugs is preferred to avoid worsening thyrotoxicosis after RAIT. MMI is preferred over PTU as pretreatment because of decreased relapse, but it is held 3 to 5 days before therapy (3)[A].
- Usually patients become hypothyroid 2 to 3 months after RAIT; therefore, antithyroid medications are continued after ablation.
- Glucocorticoids: reduce the conversion of active T4 to the more active T3. In Graves ophthalmopathy, the use of prednisone before and after RAIT prevents worsening ophthalmopathy (3)[B].
- Smoking in GD patients is a risk factor for ophthalmopathy, especially after RAIT.
- For GD, due to the chance of remission, 12- to 18-month trial of antithyroid medications may be considered prior to offering RAIT.
- For TMNG, the treatment of choice is RAIT. Medical therapy with antithyroid medications has shown a high recurrence rate. Surgery is considered only in special cases (3)[B].
- For amiodarone-induced thyrotoxicosis (AIT) type I, the treatment is antithyroid drugs and β-blockers. Thyroidectomy is the last option. AIT type II is self-limited but may use glucocorticoids.
MEDICATION
First Line
- Antithyroid drugs: MMI and PTU are thionamides that inhibit iodine oxidation, organification, and iodotyrosine coupling. PTU can block peripheral conversion of T4 to active T3. Both can be used as primary treatment for GD and prior to RAIT or surgery (1)[A].
- Duration of treatment: 12 to 18 months; 50-60% relapse after stopping; treatment beyond 18 months did not show any further benefit on remission rate. The most serious side effects are hepatitis (0.1-0.2%), vasculitis, and agranulocytosis; baseline CBC recommended:
- MMI (preferred): adults: 10 to 15 mg q12-24h; children aged 6 to 10 years: 0.4 mg/kg/day PO once daily
- PTU: adults (preferred in thyroid storm and 1st trimester of pregnancy): 100 to 150 mg PO q8h, not to exceed 200 mg/day during pregnancy
- β-Adrenergic blocker: Propranolol in high doses (>160 mg/day) inhibits T3 activation by up to 30%. Atenolol, metoprolol, and nadolol can be used.
- Glucocorticoids: reduce the conversion of active T4 to the more active T3
- Cholestyramine: anion exchange resin that decreases thyroid hormone reabsorption in the enterohepatic circulation; dose: 4 g QID (1)[B]
- Other agents:
- Lithium: inhibits thyroid hormone secretion and iodotyrosine coupling; use is limited by toxicity
- Lugol solution or saturated solution of potassium iodide (SSKI); blocks release of hormone from the gland but should be administered at least 1 hour after thionamide was given; otherwise, acts as a substrate for hormone production (Jod-Basedow effect)
- RAIT: See "Treatment" section.
ISSUES FOR REFERRAL
Patients with Graves ophthalmopathy should be referred to an experienced ophthalmologist.
SURGERY/OTHER PROCEDURES
Thyroidectomy for compressive symptoms, masses, and thyroid malignancy may be performed in the 2nd trimester of pregnancy only.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Repeat thyroid tests q3mo, CBC and LFTs on thionamide therapy; continue therapy with thionamides for 12 to 18 months.
- After RAIT, thyroid function tests at 6 weeks, 12 weeks, 6 months, and annually thereafter if euthyroid; TSH may remain undetectable for months even after patient is euthyroid; follow T3 and T4.
DIET
Sufficient calories to prevent weight loss
PROGNOSIS
Good (with early diagnosis and treatment)
COMPLICATIONS
- Surgery: hypoparathyroidism, recurrent laryngeal nerve damage, and hypothyroidism
- RAIT: postablation hypothyroidism
- GD: high relapse rate with antithyroid drug as primary therapy
- Graves ophthalmopathy, worsening heart failure if cardiac condition, atrial fibrillation, muscle wasting, proximal muscle weakness, increased risk of cerebrovascular accident (CVA) and cardiovascular mortality
REFERENCES
11 Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and the American Association of Clinical Endocrinologists. Thyroid. 2011;21(6):593-646.22 Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295(9):1033-1041.33 Abraham P, Avenell A, Park CM, et al. A systematic review of drug therapy for Graves' hyperthyroidism. Eur J Endocrinol. 2005;153(4):489-498.
CODES
ICD10
- E05.90 Thyrotoxicosis, unspecified without thyrotoxic crisis or storm
- E05.20 Thyrotxcosis w toxic multinod goiter w/o thyrotoxic crisis
- E06.1 Subacute thyroiditis
- E06.3 Autoimmune thyroiditis
- E05.10 Thyrotxcosis w toxic sing thyroid nodule w/o thyrotxc crisis
- E05.21 Thyrotxcosis w toxic multinodular goiter w thyrotoxic crisis
- E05.91 Thyrotoxicosis, unspecified with thyrotoxic crisis or storm
- E05.01 Thyrotoxicosis w diffuse goiter w thyrotoxic crisis or storm
- E06.5 Other chronic thyroiditis
- E05.81 Other thyrotoxicosis with thyrotoxic crisis or storm
- E05.40 Thyrotoxicosis factitia without thyrotoxic crisis or storm
- E05.11 Thyrotxcosis w toxic single thyroid nodule w thyrotxc crisis
- E05.00 Thyrotoxicosis w diffuse goiter w/o thyrotoxic crisis
- E05.31 Thyrotxcosis from ectopic thyroid tissue w thyrotoxic crisis
- E05.80 Other thyrotoxicosis without thyrotoxic crisis or storm
- E05.41 Thyrotoxicosis factitia with thyrotoxic crisis or storm
- E06.9 Thyroiditis, unspecified
ICD9
- 242.90 Thyrotoxicosis without mention of goiter or other cause, and without mention of thyrotoxic crisis or storm
- 242.20 Toxic multinodular goiter without mention of thyrotoxic crisis or storm
- 245.1 Subacute thyroiditis
- 245.2 Chronic lymphocytic thyroiditis
- 242.10 Toxic uninodular goiter without mention of thyrotoxic crisis or storm
- 242.01 Toxic diffuse goiter with mention of thyrotoxic crisis or storm
- 242.30 Toxic nodular goiter, unspecified type, without mention of thyrotoxic crisis or storm
- 242.00 Toxic diffuse goiter without mention of thyrotoxic crisis or storm
- 242.91 Thyrotoxicosis without mention of goiter or other cause, with mention of thyrotoxic crisis or storm
- 242.41 Thyrotoxicosis from ectopic thyroid nodule with mention of thyrotoxic crisis or storm
- 242.31 Toxic nodular goiter, unspecified type, with mention of thyrotoxic crisis or storm
- 242.81 Thyrotoxicosis of other specified origin with mention of thyrotoxic crisis or storm
- 242.21 Toxic multinodular goiter with mention of thyrotoxic crisis or storm
- 242.11 Toxic uninodular goiter with mention of thyrotoxic crisis or storm
SNOMED
- 34486009 hyperthyroidism (disorder)
- 26389007 toxic multinodular goiter (disorder)
- 38727009 subacute thyroiditis (disorder)
- 21983002 Hashimoto thyroiditis (disorder)
- 237498007 Toxic goiter
- 57777000 toxic nodular goiter (disorder)
- 90739004 thyrotoxicosis (disorder)
CLINICAL PEARLS
- Not all thyrotoxicoses are secondary to hyperthyroidism.
- GD presents with hyperthyroidism, ophthalmopathy, and goiter.
- Medical treatment for GD has a high relapse rate after stopping medications.
- Thyroid storm is a medical emergency that needs hospitalization and aggressive treatment.
- Serum TSH level may be misleading and remain low in the early period after initating treatment, even when T4 and T3 levels have decreased.